Abstract
In physiological conditions, the activity of the intestinal immune system is tightly regulated to prevent tissue-damaging reactions directed against components of the luminal flora. Various factors contribute to maintain immune homeostasis and diminished production and/or function of such molecules trigger and/or propagate detrimental signals, which can eventually lead to chronic colitis and colon cancer. One such a molecule is transforming growth factor-β1 (TGF-β1), a cytokine produced by many inflammatory and non-inflammatory cells and targeting virtually all the intestinal mucosal cell types, with the down-stream effect of activating intracellular Smad2/3 proteins and suppressing immune reactions. In patients with inflammatory bowel diseases (IBD), there is defective TGF-β1/Smad signaling due to high Smad7, an inhibitor of TGF-β1 activity. Indeed, knockdown of Smad7 with a specific antisense oligonucleotide restores endogenous TGF-β1 activity, thereby inhibiting inflammatory pathways in patients with IBD and colitic mice. Consistently, mice over-expressing Smad7 in T cells develop severe intestinal inflammation in various experimental models. Smad7 expression is also upregulated in colon cancer cells, in which such a protein controls positively intracellular pathways that sustain neoplastic cell growth and survival. We here review the role of TGF-β1 and Smad7 in intestinal immunity, inflammation, and cancer.
Highlights
The gastrointestinal tract harbors a large number of commensal bacterial, viral, and fungal species, which trigger maturation of the mucosal immune system
Using the T cell-transfer model of colitis, we showed that adoptive transfer of Smad7 Tg naïve CD4+ T cells into immunodeficient mice produced a more severe intestinal inflammation than that documented in mice reconstituted with wild-type cells, and colitis induced by Smad7 Tg cells was only partly inhibited by co-transfer of Tregs [75]
The findings discussed in this review underline the crucial role of transforming growth factor-β1 (TGF-β1) in the maintenance of intestinal homeostasis and suggest that defective function of this cytokine can contribute to trigger and/or amplify detrimental signals in the gut
Summary
The gastrointestinal tract harbors a large number of commensal bacterial, viral, and fungal species, which trigger maturation of the mucosal immune system. Besides its inhibitory effect on TGFβ1 signaling, Smad7 regulates the expression and function of several molecules involved in the control of inflammation and carcinogenesis in a TGF-β1-independent manner (Figure 1).
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